Vulnerability for substance misuse is highest among youth who experience multiple contextual risks, such as birth-related risks and socioeconomic disadvantage, during early development. Indeed, cumulative risk, defined as the number of contextual risk factors independent of the presence or absence of any particular risk, is a robust predictor of adolescent and young adult substance misuse. However, there are significant gaps in knowledge about the associations of cumulative contextual risk with substance misuse. Cumulative risk often has been studied as a static phenomenon, therefore the degree to which such risk accumulates both within and across time is unknown. Moreover, research in the cumulative risk tradition typically has examined substance misuse as a singular outcome, yet substance misuse often co-occurs with externalizing and internalizing problems. Importantly, potential mediating mechanisms and moderating influences infrequently have been considered in analyses of cumulative risk effects on substance misuse, and gender moderation rarely has been tested. Substance misuse is a prevalent public health concern, and substance misuse comorbidity is associated with heightened impairment compared to singular problems; thus, additional research is needed. The current grant application helps address these gaps by proposing to study cumulative contextual risk both within and across time during early development in relation to substance misuse and co- occurring externalizing and internalizing problems in adolescence and early adulthood (Aim 1). Social developmental mediators will be examined as intervening mechanisms (Aim 2a) and tests of social developmental moderators hypothesized to buffer risk (Aim 2b) will be conducted using existing longitudinal data from the 1986 Northern Finland Birth Cohort Study (NFBCS). The NFBCS is a large-scale birth cohort study with multi-informant (parent, teacher, adolescent), multi-source (surveys, population registries) data collected on a sample of 9,432 youth followed from the prenatal period to the 20s. Guided by the social development model (SDM), the central hypotheses are that there will be positive associations of cumulative risk with adolescent and young adult substance misuse and co-occurring problems, and that those associations will be mediated through SDM risk processes; SDM protective factors will serve as buffering moderators. Gender differences also will be explored. This application is highly innovative. The NFBCS is a unique, large-scale birth cohort study with an exceptionally broad range of biopsychological and social contextual assessments ideal for studying general risk and resilience processes. Aims of the proposed study will be accomplished by an interdisciplinary team of investigators from both university and service provider settings to facilitate translation of findings into practice. Study findings hold promise for helping to promote resilience in the face of risk among vulnerable youth by elucidating potentially malleable mediators and moderators to target in selective preventive interventions.